Mitotane treatment in patients with metastatic testicular Leydig cell tumor associated with severe androgen excess.

Mitotane (o,p'DDD) is established in the adjuvant and advanced-stage treatment of adrenocortical carcinoma and counteracts both tumor growth and tumor-related steroid production. Both the adrenal glands and the gonads are steroidogenically active organs and share a common embryogenic origin. Here, we describe the effects of mitotane in two patients with metastatic Leydig cell tumor (LCT) of the testes and associated severe androgen excess (serum testosterone 93 and 88 nmol/L, respectively; male reference range 7-27 nmol/L). Both men suffered from severe restlessness, insomnia and irritability, which they described as intolerable and disrupting normal life activities. Urinary steroid profiling by gas chromatography-mass spectrometry (GC-MS) confirmed excess androgen production and revealed concurrent overproduction of glucocorticoids and glucocorticoid precursors, which under physiological conditions are produced only by the adrenal glands but not by the gonads. In a palliative approach, they were commenced on mitotane, which achieved swift control of the hormone excess and the debilitating clinical symptoms, restoring normal quality of life. GC-MS demonstrated normalization of steroid production and decreased 5α-reductase activity, resulting in decreased androgen activation, and imaging demonstrated disease stabilization for 4-10 months. In conclusion, mitotane can be highly effective in controlling steroid excess in metastatic LCTs, with anti-tumor activity in some cases.

A randomised phase 2 trial of intensive induction chemotherapy (CBOP/BEP) and standard BEP in poor-prognosis germ cell tumours (MRC TE23, CRUK 05/014, ISRCTN 53643604).

BACKGROUND: Standard chemotherapy for poor-prognosis metastatic nonseminoma has remained bleomycin, etoposide, and cisplatin (BEP) for many years; more effective regimens are required. OBJECTIVE: To explore whether response rates with a new intensive chemotherapy regimen, CBOP/BEP (carboplatin, bleomycin, vincristine, cisplatin/BEP), versus those in concurrent patients treated with standard BEP justify a phase 3 trial. DESIGN, SETTING, AND PARTICIPANTS: We conducted a phase 2 open-label randomised trial in patients with germ cell tumours of any extracranial primary site and one or more International Germ Cell Cancer Collaborative Group poor-prognosis features. Patients were randomised between 2005 and 2009 at 16 UK centres. INTERVENTION: BEP (bleomycin 30,000 IU) was composed of four cycles over 12 wk. CBOP/BEP was composed of 2×CBOP, 2×BO, and 3×BEP (bleomycin 15,000 IU). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary end point was favourable response rate (FRR) comprising complete response or partial response and normal markers. Success required the lower two-sided 90% confidence limit to exclude FRRs <60%; 44 patients on CBOP/BEP gives 90% power to achieve this if the true FRR is ≥80%. Equal numbers were randomised to BEP to benchmark contemporary response rates. RESULTS AND LIMITATIONS: A total of 89 patients were randomised (43 CBOP/BEP, 46 BEP); 40 and 41, respectively, completed treatment. CBOP/BEP toxicity, largely haematologic, was high (96% vs 63% on BEP had Common Terminology Criteria for Adverse Events v.3 grade ≥3). FRRs were 74% (90% confidence interval [CI], 61-85) with CBOP/BEP, 61% with BEP (90% CI, 48-73). After a median of 58-mo follow-up, 1-yr progression-free survival (PFS) was 65% and 43%, respectively (hazard ratio: 0.59; 95% CI, 0.33-1.06); 2-yr overall survival (OS) was 67% and 61%. Overall, 3 of 14 CBOP/BEP and 2 of 18 BEP deaths were attributed to toxicity, one after an overdose of bleomycin during CBOP/BEP. The trial was not powered to compare PFS. CONCLUSIONS: The primary outcome was met, the CI for CBOP/BEP excluding FRRs <61%, but CBOP/BEP was more toxic. PFS and OS data are promising but require confirmation in an international phase 3 trial. PATIENT SUMMARY: In this study we tested a new, more intensive way to deliver a combination of drugs often used to treat men with testicular cancer. We found that response rates were higher but that the CBOP/BEP regimen caused more short-term toxicity. Because most patients are diagnosed when their cancer is less advanced, it took twice as long to complete the trial as expected. Although we plan to carry out a larger trial, we will need international collaboration. TRIAL REGISTRATION: ISRCTN53643604; http://www.controlled-trials.com/ISRCTN53643604.

Metastatic serous carcinoma of the testis: a case report and review of the literature.

Serous tumours of the testis and paratestis are rare, with fewer than 50 cases reported in the literature. The majority of the reported cases have been borderline serous tumours, and these tend not to recur or metastasize. Conversely, serous carcinomas can metastasize but this is often a late event. The presence of invasion in an otherwise borderline tumour has also been associated with the development of metastatic disease several years later, thus highlighting the importance of extensive sampling of all cases of borderline serous tumours. We report a case of a young man diagnosed with serous carcinoma of the testis, occurring 18 years after first diagnosis of a testicular germ cell tumour in the contralateral testis. This pattern has not previously been reported.

Biology of germ cell tumors.

Testicular cancer has been a model for a curable malignancy. The existence of an array of potential new therapies is the result of a prodigious effort in the researching and defining of the molecular components of the cancer phenotype and the subsequent rational design of agents to target candidate pathways. A better understanding of the molecular biology of cancer may also aid in guiding the most appropriate use of existing therapies, such as conventional chemotherapy.

The role of maintenance pemetrexed in the treatment of non-small-cell lung cancer.

Until recently, the weight of evidence has supported the discontinuation of chemotherapy in advanced non-small-cell lung cancer (NSCLC) after 4-6 cycles of induction therapy. This allows patients with limited life expectancy a "treatment holiday." A minority of cases then go on to receive second-line therapy, although many deteriorate rapidly and never receive further active treatment. There has been renewed interest in the concept of maintenance from trials with pemetrexed and erlotinib. Both these agents can be given for long periods without serious cumulative toxicity in most patients. Both trials have shown significant extension of progression free survival in placebo-controlled trials. In cases who are not receiving pemetrexed as induction therapy, a statistically significant 5-month prolongation of overall survival in nonsquamous NSCLC has been reported. Treatment was well tolerated. This effect may reflect the early administration of an active second-line agent and it remains to be seen whether similar benefits will accrue to patients having pemetrexed as induction therapy.

Biology of testicular germ cell tumors.

Germ cell tumors are derived from cells of the germ cell lineage and are the most common solid malignancies to affect young Caucasian men between the ages of 15 and 40 years. All testicular germ cell tumors develop from the same precursor lesion, intratubular germ cell neoplasia unclassified, which in turn is thought to arise from malignant transformation of a primordial germ cell or gonocyte. These tumors are characterized by extreme chemosensitivity and are considered a model for curative disease. In spite of this, a small subset of patients with metastatic disease fail to achieve a complete response with cisplatin-based chemotherapy or relapse from complete remission. Understanding the molecular biology may help the design of new therapies for those patients with a poor prognosis and could also improve the treatment of cancer in general. Current understanding of the role of genetic and epigenetic factors in the etiology of germ cell tumors and the biochemical mechanisms underlying chemotherapy sensitivity and resistance is discussed in detail in this review.

Management of metastatic germ cell tumors.

Germ cell tumors are the most common solid malignancies to affect young adult men and incidence is increasing worldwide. The introduction of cisplatin-based combination chemotherapy in the late 1970s resulted in a dramatic improvement in the prognosis of patients with metastatic germ cell tumors, and overall cure rates in this group now exceed 80%. Randomized clinical trials and prognostic factors have guided treatment strategies over the last two decades. Clinical research for most advanced adult malignant diseases is driven by the need to improve response rates and prolong survival. The remarkable chemotherapy sensitivity of testicular germ cell cancers has revolutionized treatment results in the last 20 years, substantially altering the landscape in these tumors with greater than 80% cure rates routinely achievable. Furthermore, it seems unlikely that modifications in dose or scheduling of currently available drugs will improve the outlook for the small minority of poor-prognosis metastatic disease cases. Failing this there are real changes in our approach to these tumors that could enhance outcomes, including better supportive care, better service delivery and better public education. The choice of different platinum, and total dose of etoposide and bleomycin and their impact on the clinical outcome in context of various trials is discussed in detail in this review.

Rational selection of patients for antibacterial prophylaxis after chemotherapy.

PURPOSE: The SIGNIFICANT (Simple Investigation in Neutropenic Individuals of the Frequency of Infection after Chemotherapy +/- Antibiotic in a Number of Tumours) trial reported a reduction in febrile episodes (FEs) among 1,565 patients with solid cancers and lymphomas receiving cyclical, myelosuppressive chemotherapy (causing grade 4 neutropenia) in a randomized, placebo-controlled, double-blind trial of levofloxacin (P = .01). In response to concerns that increased antibacterial prescribing selects for microbial resistance, we examined our data to explore the rationale for more limited prophylaxis. PATIENTS AND METHODS: The risk of FE was calculated for control patients on first versus nonfirst cycles, with or without first-cycle FE, and within subgroups defined by cancer type, performance status (PS), age, and treatment context (adjuvant v nonadjuvant). Using the randomized trial data, the prophylactic efficacy of levofloxacin was examined for the same subgroups. RESULTS: The per-cycle FE incidence was much lower on nonfirst (3.3%) versus first cycles (8.0%). Prophylaxis was less effective for nonfirst (odds ratio [OR] = 0.78; P = .16) compared with first cycles (OR = 0.42; P < .001). However, FE on cycle 1 predicted a much higher risk of FE and a trend to continued prophylactic efficacy on subsequent cycles. FE rate was greatest for testicular cancer (27.9%), then small-cell lung cancer (17.3%), and lowest for breast cancer (11.5%). Prophylactic efficacy was consistent across age, sex, PS, treatment context, and disease type (except possibly non-Hodgkin's lymphoma). CONCLUSION: Under pressure to limit antibacterial use, these exploratory data support offering prophylactic levofloxacin on cycle 1 only of myelosuppressive cancer chemotherapy and on subsequent cycles after a cycle-1 fever. Prophylactic levofloxacin is effective regardless of age, PS, or tumor type.

Upper gastrointestinal hemorrhage as a rare extragonadal presentation of seminoma of testis.

A rare case of a gastric presentation of a seminoma with burned out primary testicular tumor is described. The patient initially presented with upper gastrointestinal hemorrhage. Endoscopic biopsies were suggestive of seminoma, and testicular ultrasound revealed a focal lesion and testicular microcalcification. Treatment consisted of bilateral orchidectomy, followed by four cycles of etoposide and bleomycin, where a complete response was achieved. Testicular histology was consistent with the "burned out" phenomenon and no tumor cells were found. There are only two previously reported cases of extragonadal seminoma in the stomach.

Comparison of ABVD and alternating or hybrid multidrug regimens for the treatment of advanced Hodgkin's lymphoma: results of the United Kingdom Lymphoma Group LY09 Trial (ISRCTN97144519).

PURPOSE: To perform an open-label, randomized, controlled trial comparing treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with two multidrug regimens (MDRs) for advanced Hodgkin's lymphoma (HL). PATIENTS AND METHODS: Eight hundred seven patients with advanced HL (stage III to IV, or earlier stage with systemic symptoms or bulky disease) were randomly assigned between ABVD and MDR specified before randomization as alternating chlorambucil, vinblastine, procarbazine, and prednisolone (ChlVPP) with prednisolone, doxorubicin, bleomycin, vincristine, and etoposide (PABIOE), or hybrid ChlVPP/etoposide, vincristine, and doxorubicin (EVA). Radiotherapy was planned for incomplete response or initial bulk disease. RESULTS: At 52 months median follow-up, 212 event-free survival (EFS) events (disease progression or any death) were reported. In the primary comparison, at 3 years EFS was 75% (95% CI, 71% to 79%) for ABVD and 75% (95% CI, 70% to 79%) for MDRs (hazard ratio [HR] = 1.05; 95% CI, 0.8 to 1.37; HR more than 1.0 favors ABVD). The 3-year overall survival (OS) rates were 90% (95% CI, 87% to 93%) in patients allocated ABVD and 88% (95% CI, 84% to 91%) in patients allocated MDRs (HR = 1.22; 95% CI, 0.84 to 1.77). Patients receiving MDRs experienced more grade 3/4 infection, mucositis, and neuropathy. One occurrence of myelodysplastic syndrome was reported, but no acute leukemia was reported. When the two MDRs are compared separately with ABVD, neither the alternating nor the hybrid regimen showed a statistically significant difference from ABVD for EFS or OS. Subgroup analysis suggested that MDRs may be associated with poorer outcomes in older patients (heterogeneity test of OS older or younger than 45 years, P = .020). CONCLUSION: There was no evidence of significant difference in EFS or OS between ABVD and MDRs in the trial overall or if the two MDR versus ABVD comparisons are considered separately. ABVD remains the standard for treatment of advanced HL.